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Use of interleukin (IL-6) inhibitors has become one of the most complicated clinical issues in treating coronavirus disease 2019 (COVID-19). Recently, randomized open-label platform trials have found that IL-6 inhibitors have a beneficial effect on mortality in severe COVID-19. However, several questions arise around their mechanism of action in this disease, as well as how, when, and at which dose they should be used. IL-6 has both proinflammatory and anti-inflammatory effects, which may modulate the course of COVID-19, whose immunopathogenesis is driven by the innate immune system, autoantibodies, and interferon. Given that patients with delayed seroconversion against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein would be at the highest risk of complications beyond the second week of disease, we propose that considering patient serostatus at admission could optimize the use of IL-6 inhibitors in COVID-19. We predict that the net treatment benefits could be higher in the subgroup of patients with delayed seroconversion as compared to those who seroconvert more rapidly after SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Abstract Plasmodium parasites that infect humans are highly polymorphic, and induce various infections ranging from an asymptomatic state to life-threatening diseases. However, how the differences between the parasites affect host immune responses during blood-stage infection remains largely unknown. We investigated the CD4+ T-cell immune responses in mice infected with P. berghei ANKA (PbA) or P. chabaudi chabaudi AS (Pcc) using PbT-II cells, which recognize a common epitope of these parasites. In the acute phase of infection, CD4+ T-cell responses in PbA-infected mice showed a lower involvement of Th1 cells and a lower proportion of Ly6Clo effector CD4+ T cells than those in Pcc-infected mice. Transcriptome analysis of PbT-II cells indicated that type I interferon (IFN)-regulated genes were expressed at higher levels in both Th1- and Tfh-type PbT-II cells from PbA-infected mice than those from Pcc-infected mice. Moreover, IFN-α levels were considerably higher in PbA-infected mice than in Pcc-infected mice. Inhibition of type I IFN signaling increased PbT-II and partially reversed the Th1 over Tfh bias of the PbT-II cells in both PbA- and Pcc-infected mice. In the memory phase, PbT-II cells in PbA-primed mice maintained higher numbers and exhibited a better recall response to the antigen. However, recall responses were not significantly different between the infection groups after re-challenge with PbA, suggesting the effect of the inflammatory environment by the infection. These observations suggest that the differences in Plasmodium -specific CD4+ T-cell responses between PbA- and Pcc-infected mice were associated with the difference in type I IFN production during the early phase of the infection. [ABSTRACT FROM AUTHOR]

Upon activation, specific CD4+ T cells up-regulate the expression of CD11a and CD49d, surrogate markers of pathogen-specific CD4+ T cells. However, using T-cell receptor transgenic mice specific for a Plasmodium antigen, termed PbT-II, we found that activated CD4+ T cells develop not only to CD11ahiCD49dhi cells, but also to CD11ahiCD49dlo cells during acute Plasmodium infection. CD49dhi PbT-II cells, localized in the red pulp of spleens, expressed transcription factor T-bet and produced IFN-γ, indicating that they were type 1 helper T (Th1)-type cells. In contrast, CD49dlo PbT-II cells resided in the white pulp/marginal zones and were a heterogeneous population, with approximately half of them expressing CXCR5 and a third expressing Bcl-6, a master regulator of follicular helper T (Tfh) cells. In adoptive transfer experiments, both CD49dhi and CD49dlo PbT-II cells differentiated into CD49dhi Th1-type cells after stimulation with antigen-pulsed dendritic cells, while CD49dhi and CD49dlo phenotypes were generally maintained in mice infected with Plasmodium chabaudi. These results suggest that CD49d is expressed on Th1-type Plasmodium -specific CD4+ T cells, which are localized in the red pulp of the spleen, and can be used as a marker of antigen-specific Th1 CD4+ T cells, rather than that of all pathogen-specific CD4+ T cells. [ABSTRACT FROM AUTHOR]

Early-life exposures to environmental insults can misprogram development and increase metabolic disease risk in a sex-dependent manner by mechanisms that remain poorly characterized. Modifiable factors of increasing public health relevance, such as diet, psychological stress, and endocrine-disrupting chemicals, can affect glucocorticoid receptor signaling during gestation and lead to sex-specific postnatal metabolic derangements. Evidence from humans and animal studies indicate that glucocorticoids crosstalk with sex steroids by several mechanisms in multiple tissues and can affect sex-steroid–dependent developmental processes. Nonetheless, glucocorticoid sex-steroid crosstalk has not been considered in the glucocorticoid-induced misprogramming of metabolism. Herein we review what is known about the mechanisms by which glucocorticoids crosstalk with estrogen, androgen, and progestogen action. We propose that glucocorticoid sex-steroid crosstalk is an understudied mechanism of action that requires consideration when examining the developmental misprogramming of metabolism, especially when assessing sex-specific outcomes. [ABSTRACT FROM AUTHOR]

As long as a square non-negative matrix A has total support then it can be balanced, that is, we can find a diagonal scaling of A that has row and column sums equal to one. A number of algorithms have been proposed to achieve the balancing, the most well known of these being Sinkhorn–Knopp. In this paper, we derive new algorithms based on inner–outer iteration schemes. We show that Sinkhorn–Knopp belongs to this family, but other members can converge much more quickly. In particular, we show that while stationary iterative methods offer little or no improvement in many cases, a scheme using a preconditioned conjugate gradient method as the inner iteration converges at much lower cost (in terms of matrix–vector products) for a broad range of matrices; and succeeds in cases where the Sinkhorn–Knopp algorithm fails. [ABSTRACT FROM AUTHOR]

Murine cerebral malaria is a complex disease caused by Plasmodium berghei ANKA infection. Several cell types, including CD8+ T cells, are essential effectors of disease. Although the use of transgenic parasites expressing model antigens has revealed the induction of cytotoxic T lymphocytes (CTL) specific for these model antigens, there is no direct evidence for a response to authentic blood-stage parasite antigens, nor any knowledge of its magnitude. Our studies show that there is a dramatic primary parasite-specific CTL response, akin to viral immunity, reaching approximately 30% of splenic CD8+ T cells, with many producing interferon-&ggr; and tumor necrosis factor-&agr;. These cells express granzyme B and other markers of specific responders, are cytolytic, and respond to a broad array of major histocompatibility complex (MHC) I-restricted epitopes, 5 of which are identified here. Our studies indicate that vigorous CTL responses can be induced to pathogens even when they largely reside in red blood cells, which lack MHC I processing machinery. [ABSTRACT FROM AUTHOR]

A crucial step in inbred plant breeding is the choice of mating design to derive high-performing inbred varieties while also maintaining a competitive breeding population to secure sufficient genetic gain in future generations. In practice, the mating design usually relies on crosses involving the best parental inbred lines to ensure high mean progeny performance. This excludes crosses involving lower performing but more complementary parents in terms of favorable alleles. We predicted the ability of crosses to produce putative outstanding progenies (high mean and high variance progeny distribution) using genomic prediction models. This study compared the benefits and drawbacks of 7 genomic cross selection criteria (CSC) in terms of genetic gain for 1 trait and genetic diversity in the next generation. Six CSC were already published, and we propose an improved CSC that can estimate the proportion of progeny above a threshold defined for the whole mating plan. We simulated mating designs optimized using different CSC. The 835 elite parents came from a real breeding program and were evaluated between 2000 and 2016. We applied constraints on parental contributions and genetic similarities between selected parents according to usual breeder practices. Our results showed that CSC based on progeny variance estimation increased the genetic value of superior progenies by up to 5% in the next generation compared to CSC based on the progeny mean estimation (i.e. parental genetic values) alone. It also increased the genetic gain (up to 4%) and/or maintained more genetic diversity at QTLs (up to 4% more genic variance when the marker effects were perfectly estimated). [ABSTRACT FROM AUTHOR]